Catalytic activity of reusable nickel oxide nanoparticles in the synthesis of spirooxindoles

Abstract

This study focuses on nickel oxide nanoparticles as efficient nanocatalysts in the synthesis of oxindoles as an important class of potentially bioactive compounds. The oxindole derivatives were prepared by the condensation of malononitrile, 1,3-dicarbonyl/4-hydroxycoumarine and isatin compounds in water, an excellent solvent in terms of environmental impact and reduction waste production.

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Introduction

Recently, great attention has also been focused from both environmental and economical points on the use of heterogeneous solid acid catalysts for various organic transformations.^1,2 Heterogeneous catalysts are always superior to their homogeneous counterparts in terms of many aspects such as operational simplicity, reusability, environmental compatibility and high selectivity. With the advancement of nanoscience and nanotechnology, nanoparticulate heterogeneous catalysts have received notable attention in organic transformations on the grounds of their ability to enhance faster rates of organic reactions, their high catalytic activity and higher yield of products which is due to their ability to afford a high particle size-to-volume ratio along with greater surface area.³ During recent years, nickel oxide nanoparticles have attracted much attention as inexpensive and nonhazardous catalysts or effective promoters that can enhance the reactivity and selectivity of various organic reactions.^4,5

On a different note, indoline and oxindole which are important fragments of a large number of natural products and medicinal agents have shown good biological activity.^6–11 Oxindoles are known to possess antibacterial, antiprotozoal and anti-inflammatory activities and are also patented as PR (progesterone receptors) agonists.^12,13 Among the oxygen-containing heterocycles fused with spirooxindole ring system, chromenes are of particular utility as they belong to ‘privileged medicinal scaffolds’—certain molecular frameworks serving for the generation of ligands for functionally and structurally discreet biological receptors.¹⁴ Functionally substituted 4H-chromenes have received considerable attention due to their wide range of useful biological properties, which include spasmolitic, diuretic, anticoagulant, anticancer, and antianaphylactic activities.¹⁵

In many cases, organic solvents which are used in huge amounts for many different applications have a negative impact on the health and the environment. One of the key areas of green chemistry is the elimination of solvents in chemical processes or the replacement of hazardous solvents with environmentally benign solvents. Water emerged as a useful alternative solvent for several organic reactions owing to many of its potential advantages such as safety, economy and environmental concern. Sometimes it shows higher reactivity and selectivity compared to other conventional organic solvents due to its strong hydrogen bonding ability.^16,17

Due to the pharmacological properties of oxindoles, development of synthetic methods enabling easy access to these compounds are desirable. In continuation of our work on the synthesis of biologically important compounds using simple, efficient and nontoxic catalysts,^18–22 in this paper we report synthesis of spirocyclic (5,6,7,8-tetrahydro-4H-chromene)-4,3′-oxindole and dihydro[pyrano[3,2-c]quinoline]-4,3-indoline derivatives by the coupling of malononitrile, 1,3-dicarbonyl/4-hydroxycoumarine and isatin derivatives in the presence of nano-NiO as an inexpensive and efficient catalyst in aqueous medium (Scheme 1).

Scheme 1

Results and discussion

Characterization of nickel oxide nanoparticles

Initially, nickel oxide nanoparticles were synthesized by the reaction of nickel nitrate hexahydrate with urea in deionized water and was heated at 115 °C for 1.5 h in an oil bath. Resulting compound was dried and was calcined in at 400 °C for 1 h. Then Nano NiO were characterized by XRD, EDS and TEM.¹⁸

Application of NiO nanoparticles for the synthesis of spirooxindoles

In order to show the merit of synthesized heterogeneous catalyst in organic reactions, nano NiO was used as an efficient and inexpensive catalyst for synthesis of a series of analogues of oxindole using various isatins and dicarbonyls. 1,3-Cyclohexadione (1), isatin (2) and malononitrile (3) were selected as the model substrates and reacted under different experimental variants (Scheme 2).

Scheme 2 Synthesis of 2-amino-2′,5-dioxo-5,6,7,8-tetrahydro spiro-[chromene-4,3′-indoline]-3-carbonitrile.

Optimization of the reaction conditions

In preliminary experiment, this reaction was carried out in various solvents, with nano-NiO (0.0007 g) as a catalyst under room temperature.

The reaction proceeded perfectly in polar solvents (Table 1, entries 1–6), but the yields decreased when the reaction was carried out in nonpolar solvents (Table 1, entries 7–11). The reaction could be carried out under solvent-free conditions and gave good yield (Table 1, entry 12).

Table 1 Effect of solvents on the synthesis of oxindole catalyzed by nano-NiO^a

Entry	Solvent	Yield^b (%)
a Reaction conditions: reagents (1 mmol), catalyst (0.0007 g), solvent (2 mL) for 5 min.b Isolated yields.
1	H2O	98
2	EtOH	85
3	MeOH	88
4	EtOAc	85
5	DMSO	93
6	DMF	90
7	CH3CN	70
8	ClCH2CH2Cl	68
9	THF	50
10	CHCl3	62
11	CH2Cl2	55
12	Solvent-free	75

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Comparison of catalytic activities of nano-NiO and bulk metal oxides

To evaluate catalytic activity of nano-NiO, the model reaction was carried out in water (2 mL) at room temperature for 5 min in the presence of different catalytic systems (0.0007 g), separately. The results are shown in Table 2. As it is evident from the results, nano-NiO was the most effective catalyst in terms of yield of the oxindole (98%) while other catalysts formed the product with the yields of 5–38% (Table 2, entries 1–9).

Table 2 Synthesis of oxindole in the presence of various catalytic systems^a

Entry	Catalyst	Yield^b (%)
a Reaction conditions: 1,3-cyclohexadione (1 mmol), isatin (1 mmol), malononitrile (1 mmol), catalyst (0.0007 g) and H2O (2 mL) stirred at room temperature for 5 min.b Yields are related to isolated pure products.
1	SiO2	20
2	Al2O3(acidic)	18
3	Al2O3(basic)	20
4	MgO	5
5	CaO	20
6	CdO	25
7	CuO	15
8	As2O3	33
9	CrO3	38
10	Nano-NiO	98

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Extension of substrate scope

Further explore the scope and limitation of this protocol under the optimized conditions (0.0007 g catalyst in H₂O at r.t.), particularly in regard to library construction, was evaluated using various isatin and 1,3-dicarbonyl compounds (Table 3). In all cases, the reaction proceeded readily to afford the corresponding oxindoles in high to excellent yields (70–98%) in very short reaction times (5 min). The reaction of dimedone took place faster than 1,3-cyclohexadione analogues that this behavior could result from the more reactivity of dimedone by electron-donating groups (Me).

Table 3 Preparation of oxindole derivatives^a

Entry	Reactant			Yield (%)	Melting Point
	Dicarbonyl	Isatin
	R1	R2	R3
a Reaction conditions: dicarbonyl compounds (1 mmol), isatins (1 mmol), malononitrile (1 mmol), catalyst (0.0007 g), and H2O (2 mL); reactions conducted at r.t. for 5 min.
1	H	H	H	98	251–253
2	H	PhCH2	H	89	283–284
3	H	H	Cl	88	275–276
4	H	H	Br	90	289–292
5	H	H	NO2	92	279–280
6	H	H	Me	70	263–265
7	H	H	OMe	82	268–269
8	H	PhCH2	Br	71	295–296
9	H	Et	NO2	82	276–277
10	Me	Et	NO2	94	281–283
11	Me	H	Cl	91	273–274
12	Me	H	H	98	289–290
13	Me	H	OMe	78	282–283

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Due to the biological and pharmacological importance of the indoline ring system and to further expand the scope of this reaction, we also investigated reaction of 4-hydroxycoumarine instead of diketone were obtained products in excellent yields under the same reaction conditions.

Reusability of the catalyst

At the end of the reaction, the catalyst could be recovered by centrifuge. The recycled catalyst was washed with dichloromethane and subjected to a second reaction process. The results show that the yield of product after five runs was only slightly reduced (Table 5).

Table 4 Preparation of indoline derivatives^a

Entry	R1	R2	Yield (%)
a Reaction conditions: 4-hydroxycoumarine (1.0 mmol), isatins (1.0 mmol), malononitrile (1.0 mmol), catalyst (0.0007 g), and H2O (2 mL); reactions conducted at r.t.
1	H	H	96
2	H	Cl	91
3	H	Br	98
4	H	NO2	95
5	H	OMe	83
6	H	Me	82
7	Me	NO2	98
8	Et	NO2	91
9	PhCH2	Br	75
10	PhCH2	H	83

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Table 5 Recyclability of nano-NiO in the synthesis of oxindoles^a

Entry	Cycle	Yield (%)
a Reaction conditions: reagents (1 mmol), catalyst (0.0007 g), H2O (2 mL) for 5 min.
1	0	98
2	1	98
3	2	96
4	3	95
5	4	91
6	5	89

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Experimental

General methods

Malononitrile, 1,3-dicarbonyl, 4-hydroxycoumarin and isatin derivatives were purchased from Merck Chemical Company. Purity determination of the products were accomplished by TLC on silica-gel polygram SILG/UV 254 plates. Melting points were measured on an Electro thermal 9100 apparatus. IR spectra were taken on a Perkin Elmer 781 spectrometer in KBr pellets and reported in cm⁻¹. ¹H NMR and ¹³C NMR spectra were measured on a Bruker DPX-250 Avance instrument at 250 MHz and 62.9 MHz in CDCl₃ or DMSO-d₆ with chemical shift given in ppm relative to TMS as internal standard. The morphology of the products was determined by using CMPhilips10 model Transmission Electron Microscopy (TEM) at accelerating voltage of 100 KV. Power X-ray diffraction (XRD) was performed on a Bruker D₈-advance X-ray diffractometer with Cu K_α (λ = 0.154 nm) radiation.

Preparation of nano NiO

Nickel oxide nanoparticles were prepared through the following process. The molar ratio of nickel nitrate hexahydrate to urea at 1 : 4, a stoichiometric amount of Ni(NO₃)₂·6H₂O (0.08 mol) and CO(NH₂)₂ (0.32 mol) was accurately weighed and dissolved into 60 mL of deionized water, respectively. The two solutions were mixed in a beaker and stirred with a magnetic stirrer at room temperature until a homogeneous solution obtained. Thereafter, the mixture was transferred into a round bottom flask, sealed and maintained heating at 115 °C for 1.5 h in an oil bath. In this process, a kind of light green sediment (i.e., the precursor) was formed. After the reaction was completed, the precipitated powders were filtered and washed with deionized water to neutral and colorless. This was to remove the possibly adsorbed ions and chemicals to reduce the potential of agglomeration. After being dried in an oven at 90 °C for 6 h, the precursors were calcined in a muffle furnace at 400 °C for 1 h to obtain the products in dark color (i.e., NiO nanoparticles). The calcined products were then collected for further analyses.⁵

General procedure for the preparation of oxindol derivatives

A mixture of malononitrile (1 mmol), isatin (1 mmol), dicarbonyl (1 mmol), nano-NiO (0.0007 g) and water (2 mL) was stirred for the appropriate time at room temperatures, as shown in Tables 3 and 4 Completion of the reaction was indicated by TLC monitoring. After completion of the reaction, the reaction mixture was dissolved in acetone and catalyst was isolated by centrifuged. The product was afforded by evaporation of solvent and was recrystallized from EtOH to afforded the pure products in high purity and yield. Structural assignments of the products are based on their ¹H NMR, ¹³C NMR and IR spectra.

2-Assmino-2′,5-dioxo-5,6,7,8-tetrahydrospiro-[chromene-4,3′-indoline]-3-carbonitrile (compound 1, Table 3). White solid, mp > 250 °C. ¹H NMR (250 MHz, DMSO-d₆): 1.91 (2H, m, CH₂), 2.10 (2H, m, CH₂), 2.62 (2H, m, CH₂), 6.68 (d, 1H, J = 7.4 Hz, Ph), 6.88 (t, 1H, J = 7.4 Hz, Ph), 7.10 (d, 1H, J = 7.4 Hz, Ph), 7.22 (t, 1H, J = 7.4 Hz, Ph), 7.35 (s, 2H, NH₂), 10.65 (s, 1H, NH) ppm. ¹³C NMR (62.9 MHz, DMSO-d₆) 195.1(C=O), 178.2(C=O), 166.1(C), 158.7(C), 142.0(C), 134.6(C), 128.5(CH), 123.3(CH), 121.8(CH), 117.4(CH), 112.9(CN), 109.2(C), 57.6(C), 46.9(C), 36.4(CH₂), 26.8(CH₂), 19.8(CH₂). IR (KBr, cm⁻¹) 3352, 3295, 3175, 2952, 2204, 1713, 1655, 1352, 1216, 1076. Anal. calcd for C₁₇H₁₃N₃O₃: C, 66.44; H, 4.26; N, 13.67%. Found: C, 66.42; H, 4.31; N, 13.72%.

2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (compound 12, Table 3). White solid, mp > 250 °C. ¹H NMR (250 MHz, DMSO-d₆): 1.00 (3H, s, CH₃), 1.1 (3H, s, CH₃), 2.08–2.12 (2H, m, CH₂), 2.56 (2H, m, CH₂), 6.70 (d, 1H, J = 7.4 Hz, Ph), 6.88 (t, 1H, J = 7.4 Hz, Ph), 7.10 (d, 1H, J = 7.4 Hz, Ph), 7.22 (t, 1H, J = 7.4 Hz, Ph), 7.35 (s, 2H, NH₂), 10.65 (s, 1H, NH). ¹³C NMR (62.9 MHz, DMSO-d₆) 195.3(C=O), 178.5(C=O), 166.58(C), 159.20(C), 152.4(C), 142.48(C), 134.83(CH), 128.59(CH), 123.4(CH), 122.16(CH), 117.76(C), 112.22(CN), 109.7(C), 57.96(C), 50.45(CH₂), 47.23(C), 32.35(CH₂), 28.01(CH₃), 27.1(CH₃). IR (KBr, cm⁻¹): 3376, 3312, 3144, 2928, 2196, 1724, 1656, 1348, 1224, 1056 cm⁻¹. Anal. calcd for C₁₉H₁₇N₃O₃: C, 68.05; H, 5.11; N, 12.53%. Found: C, 67.86; H, 5.14; N, 12.65%.

2-Amino-2′,5-dioxo-5,6-dihydro-spiro[pyrano[3,2-c]quinoline-4,3′-indoline]-3-carbonitrile (compound 1, Table 4). White solid, mp > 250 °C. ¹H NMR (250 MHz, DMSO-d₆): 6.83 (1H, d, J = 7.6 Hz, Ph), 6.92 (1H, t, J = 7.6 Hz, Ph), 7.17 (1H, d, J = 7.2 Hz, Ph), 7.32 (1H, d, J = 7.6 Hz, Ph), 7.44 (1H, t, J = 7.6 Hz, Ph), 7.48 (1H, t, J = 8.2 Hz, Ph), 7.52 (1H, d, J = 8.4 Hz, Ph), 7.53 (2H, s, NH₂), 7.95 (1H, d, J = 8.2 Hz, Ph), 10.65 (1H, s, NH). ¹³C NMR (62.9 MHz, DMSO-d₆) 177.4(C=O), 158.9(C=O), 155.7(C), 155.5(C), 152.4(CH), 142.6(CH), 134.1(CH), 133.5(CH), 129.38(C), 125.4(C), 124.5(CH), 123.12(CH), 122.52(CH), 117.42(CH), 117.09(C), 112.9(CN), 109.9(C), 101.9(C), 70.2(C), 57.5(C). IR (KBr, cm⁻¹): 3415, 3241, 3260, 2218, 1719, 1679, 1623, 1581; Anal. calcd for C₂₀H₁₁N₃O₄: C, 67.23; H, 3.10; N, 11.76%. Found: C, 67.39; H, 3.12; N, 11.65%.

Conclusions

In summary, an efficient protocol for the preparation of spirocyclic (5,6,7,8-tetrahydro-4H-chromene)-4,3′-oxindole and dihydro[pyrano[3,2-c]quinoline]-4,3-indoline derivatives was described. The procedure offers several advantages including the cheapness and the availability of the catalyst, mild reaction conditions and high yields of the products as well as simple experimental and isolation procedures. All these, make this protocol a useful and an attractive procedure for the synthesis of oxindole and indoline derivatives.

Acknowledgements

We gratefully acknowledge the support of this work by the Birjand University research council.

References

1. B. Das, K. Venkateswarlu, H. Holla and M. Krishnaiah, J. Mol. Catal. A: Chem., 2006, 253, 107.
2. A. Shaabani, A. Rahmati and Z. Badri, Catal. Commun., 2008, 9, 13.
3. C. L. Carnes and K. J. Klabunde, J. Mol. Catal. A: Chem., 2003, 194, 227.
4. V. Biju and M. Abdul Khadar, Mater. Sci. Eng., A, 2001, 304, 814.
5. Y. Wang, J. Zhu, X. Yang, L. Lu and X. Wang, Thermochim. Acta, 2005, 437, 106.
6. R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York, 1996.
7. K. C. Joshi and P. Chand, Biologically active indole derivatives, Pharmazie, 1982, 37, 1.
8. A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna and S. M. El-Bady, Bioorg. Med. Chem., 2004, 12, 2483.
9. T. H. Kang, K. Matsumoto, M. Tohda, Y. Murakami, H. Takayama, M. Kitajima, N. Aimi and H. Watanabe, Eur. J. Pharmacol., 2002, 444, 39.
10. J. Leclercq, M. C. De Pauw Gillet, R. Bassleer and L. Angenot, J. Ethnopharmacol., 1986, 15, 305.
11. (a) J. Ma and S. M. Javaniside, Chem. Commun., 2004, 1190; (b) R. Y. Guo, Z. M. An, L. P. Mo, R. Z. Wang, H. X. Liu, S. X. Wang and Z. H. Zhang, ACS Comb. Sci., 2013, 15, 557.
12. S. Pepeljnjak, I. Jalsenjak and D. Maysinger, Pharmazie, 1982, 37, 864.
13. B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Andersons and R. S. Chang, J. Med. Chem., 1988, 31, 2235.
14. L. L. Andreani and E. Lapi, Boll. Chim. Farm., 1960, 99, 583.
15. L. Bonsignore, G. Loy and D. Secci, Eur. J. Med. Chem., 1993, 28, 517.
16. C. J. Li, Chem. Rev., 2005, 105, 3095.
17. F. Bazi, H. Badaoui, S. Tamani, S. Sokori, A. Solhy, D. J. Macquarrie and S. Sebti, Appl. Catal., A, 2006, 211, 301.
18. M. A. Nasseri, F. Ahrari and B. Zakerinasab, RSC Adv., 2015, 5, 13901.
19. M. A. Nasseri, B. Zakerinasab and M. M. Samieadel, RSC Adv., 2014, 4, 41753.
20. M. A. Nasseri, S. A. Alavi and B. Zakerinasab, J. Iran. Chem. Soc., 2013, 10, 21.
21. M. A. Nasseri and M. Salimi, Lett. Org. Chem., 2013, 10, 164.
22. M. A. Nasseri and S. M. Sadeghzadeh, J. Iran. Chem. Soc., 2014, 11, 27.

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